The present invention concerns apparatuses for transdermal delivery or transport of therapeutic agents, typically through iontophoresis. Herein the terms "electrotransport", "iontophoresis", and "iontophoretic" are used to refer to methods and apparatus for transdermal delivery of therapeutic agents, whether charged or uncharged, by means of an applied electromotive force to an agent-containing reservoir. The particular therapeutic agent to be delivered may be completely charged (ie, 100% ionized), completely uncharged, or partly charged and partly uncharged. The therapeutic agent or species may be delivered by electromigration, electroosmosis or a combination of the two. Electroosmosis has also been referred to as electrohydrokinesis, electro-convection, and electrically-induced osmosis. In general, electroosmosis of a therapeutic species into a tissue results-from the migration of solvent, in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir, ie, solvent flow induced by electromigration of other ionic species. Thus, as used herein, the terms "iontophoresis" and "iontophoretic" refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (4) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.
During the electrotransport process certain modifications or alterations of the skin may occur such as increased ionic content, hydration, dielectric breakdown, extraction of endogenous substances and electroporation. Any electrically assisted transport of species enhanced by modifications or alterations to a body surface (eg, formation of pores in the skin) are also included in the term electrotransport as used herein.
Iontophoretic devices for delivering ionized drugs through the skin have been known since the 1800's. Deutsch United Kingdom Patent No. 410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices, namely, that the patient needed to be immobilized near a source of electric current. The Deutsch device was powered by a galvanic cell formed from the electrodes and the material containing the drug to be transdermally delivered. The galvanic cell produced the current necessary for iontophoretically delivering the drug. This device allowed the patient to move around during iontophoretic drug delivery and thus required substantially less interference with the patient's daily activities.
In present iontophoresis devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, agent, medicament, drug precursor or drug is delivered into the body via the skin by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, eg, a battery; and usually to circuitry capable of controlling current passing through the device. For example, if the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve to complete the circuit. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
Furthermore, existing iontophoresis devices generally require a reservoir or source of the beneficial agent or drug, preferably an ionized or ionizable species (or a precursor of such species) which is to be iontophoretically delivered or introduced into the body. Such drug reservoirs are connected to the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired species or agents.
Perhaps the most common use of iontophoresis today is in diagnosing cystic fibrosis by delivering pilocarpine transdermally. lontophoretically delivered pilocarpine stimulates sweat production, the sweat is collected, and is analyzed for its chloride ion content. Chloride ion concentration in excess of certain limits suggests the possible presence of the disease.
Thus an electrotransport device or system, with its donor and counter electrodes, may be thought of as an electrochemical cell having two electrodes, each electrode having an associated half cell reaction, between which electrical current flows. Electrical current flowing though the electronically conductive (eg, metal) portions of the circuit is carried by electrons (electronic conduction), while current flowing through the liquid-containing portions of the device (ie, the drug reservoir in the donor electrode, the electrolyte reservoir in the counter electrode, and the patient's body) is carried by ions (ionic conduction). Current is transferred from the metal portions to the liquid phase by means of oxidation and reduction charge transfer reactions which typically occur at the interface between the metal portion (eg, a metal electrode) and the liquid phase (eg, the drug solution). A detailed description of the electrochemical oxidation and reduction charge transfer reactions of the type involved in electrically assisted drug transport can be found in electrochemistry texts such as J. S. Newman, Electrochemical Systems (Prentice Hall, 1973) and A. J. Bard and L. R. Faulkner, Electrochemical Methods, Fundamentals and Applications (John Wiley & Sons, 1980).
As electrical current flows, oxidation and reduction of a chemical species takes place. A variety of electrochemical reactions can be utilized, and these generally fall into two major classes. In one major class, the electrochemical reaction results in the generation of a mobile ionic species with a charge state (ie, + or -) like that of the drug in its ionic form. Such a mobile ionic species is referred to as a "competitive species" or a "competitive ion" because the species competes with the drug for delivery by electrotransport. Exemplifying this class of reactions is what is referred to in the art as a "sacrificial" reaction where electrode material is consumed in the reaction with generation of a competitive ion. A further example of this first major class of electrochemical reactions is a de-intercalation reaction where a competitive ion is expelled from the electrode. A third example of this first major class of electrodes is the common situation where a competitive ion is generated by oxidation or reduction of a substance in contact with the electrode. Reactions falling in the first major class may be either anodic or cathodic.
Examples of anodic reactions where a competitive cation is generated include: EQU M.sup.0.fwdarw.M.sup.Z+ +Ze.sup.- (1)
where M.sup.0 is a metal which is oxidized to the +Z state and M.sup.Z+ is the competitive ion; EQU M.sub.x WO.sub.3.fwdarw.M.sub.x-1 WO.sub.3 +M.sup.+ +e.sup.- (2)
where M.sup.+ is the competitive ion, and EQU H.sub.2 Q.fwdarw.Q.sup.0 +2H.sup.+ +2e.sup.- (3)
where Q.sup.0 is a species which is stable in its reduced state and H.sup.+ is the competitive ion.
Examples of cathodic reactions where a competitive anion is generated include: EQU AgCl+e.sup.-.fwdarw.Ag.sup.0 +Cl.sup.-. (4) EQU C.sub.n FeCl.sub.3 +e.sup.-.fwdarw.C.sub.n FeCl.sub.2 +Cl.sup.- (5)
and EQU Cl.sub.2 +2e.sup.-.fwdarw.2Cl.sup.- (6)
where Cl.sup.- is the competitive anionic species in each of reactions, 4, 5, and 6.
In a second major class of electrochemical reactions, no competitive ion is generated during the operation of the system. In one example of this class of reactions, the species to be reduced or oxidized exist in solution and the charge transfer oxidation or reduction reaction is catalyzed at the electrode surface. The products of the reaction are gaseous or soluble in the reservoir and either are neutral or exist in a charge state opposite that of the drug in its ionic form. A reaction product having a charge state opposite that of the drug to be delivered would not be "competitive" as the term is used here. Example of anodic reactions of this latter class which do not generate a competitive ion include:
Fe(CN).sub.6.sup.4-.fwdarw.Fe(CN).sub.6.sup.3- +e.sup.- (7) EQU C.sub.n FeCl.sub.2 +Cl.sup.-.fwdarw.C.sub.n FeCl.sub.3 +e.sup.-. (8)
Examples of cathodic reactions which do not generate a competitive ion include: EQU M.sup.Z+ +ze.sup.-.fwdarw.M.sup.0 (9) EQU M.sub.x-1 WO.sub.3 +M.sup.+ +e.sup.-.fwdarw.M.sub.x WO.sub.3 (10) EQU Q.sup.0 +2H.sup.+ +2e.sup.-.fwdarw.H.sub.2 Q, (11)
and EQU Fe.sup.3+ +e.sup.-.fwdarw.Fe.sup.2+. (12)
Reactions 7, 9, 11, and 12 are catalyzed by an appropriately polarized surface of a substantially inert or catalytic electrode, such as the surface of a catalytic electrode comprising carbon, gold, stainless steel or platinum. Reactions 8 and 10 are intercalation/insertion reactions where an ionic species is incorporated into the electrode material during operation of the device.
It is particularly important in attempting to determine which of the above major classes a particular system falls into, to focus upon the species generated during the electrochemical reaction(s) as it (or they) relate to the drug or agent to be delivered. In particular, the focus should be whether the species generated will electromigrate in the same direction (eg, toward the skin) as the drug or agent of choice under the influence of the electric potential gradient. In other words, it is significant that an ionic species is being produced only in so far as ionic species competes with a drug or agent to be delivered and thereby adversely impacts biocompatability of the electrotransport system (eg, where the competing ionic species produced is not biocompatible), drug stability, or drug delivery efficiency.
In the prior art, iontophoresis electrodes employing the first approach, above, have usually included current distributing members or structures referred to as "active" or "electroactive" or "electrochemically reactive" in the sense that their chemical compositions were materially altered during the agent delivery process. For example, sacrificial current distributing members which were oxidized or reduced themselves have been discussed. Use of sacrificial current distribution members can avoid the adverse effects associated with utilization of catalytic current distributing members (eg, pH changes). Electrodes with sacrificial current distributing members are disclosed in U.S. Pat. No. 4,744,787 to Phipps, et al and U.S. Pat. No. 5,135,477 to Untereker, et al. Intercalation electrodes are discussed in patents issued to those same inventors.
The current distributing member in an iontophoresis electrode employing the second approach, above, have usually been constructed to include substantially inert materials such as stainless steel or platinum. "Inert" as that term is used in the art normally means that the material is catalytic, ie, it catalyzes an oxidation or reduction reaction by providing or accepting electrons to or from other chemical species but does not itself take part in the reaction by being chemically or physically altered. The material of the electrode structure, eg, the current distributing member, therefore is "inert" only in the sense of itself not being chemically altered in the reduction or oxidation reaction in which it participates.
When oxidation or reduction occurs at an electrode surface, ionic species must be transported to maintain electroneutrality throughout the system. Electrically-assisted transport or electrotransport is defined as the mass transport of a particular chemical species through a biological interface or membrane when an electrical potential gradient is imposed across said interface or membrane. Four physical processes contribute to this transport: passive diffusion, electromigration, electroporation, and convection. Even though drug electrotransport systems are well characterized, there is a continuing need to enhance their drug delivery efficiency. Enhanced efficiency permits smaller, less expensive and more versatile devices to be developed. Optimization of the three physical transport processes is one approach to enhance such efficiency.
In the iontophoresis art, various approaches have been taken to increase the drug delivery efficiency of (ie, the amount of drug delivered per unit of applied electrical current) transdermal drug or agent delivery. This issue was addressed in U.S. Pat. No. 5,135,477 to Untereker et al and in earlier related U.S. Pat. Nos. 4,744,787 and 4,747,819 both to Phipps et al. The above patents disclose increased electrotransport drug delivery efficiency by the selection, (in accordance with the Untereker et al patent) of: (1) the particular form of the drug to be delivered, (2) an electrochemically active component of the drug delivery apparatus, or (3) both, so that during the operation of the apparatus competitive species (i.e, ions carrying the same charge as the drug ions and thus in competition with the drug for carrying current into the body) were reduced or eliminated. The basic solution proposed by Untereker et al has the drawback in that the particular agent or drug to be iontophoretically delivered may be unavailable in a form with the desired counter ion. Even if the drug is available in the proper salt form (eg, when using a silver anodic electrode, the drug is preferably in the form of a chloride salt so that the drug counter ion is chloride), the net or overall electrochemical process (Ag+Cl.sup.-.fwdarw.AgCl+e.sup.-) may require more counter ion (eg, Cl.sup.-) than can be supplied by the drug salt alone. This is particularly true for highly potent or expensive drugs, where the concentration of drug salt within the reservoir is generally relatively small. Put otherwise, a particular combination of drug/drug counter ion, and electroactive component of the device to enhance efficiency of the device in accordance with the teachings of the above patents may not be practical due to limitations on the availability of drug salt in the appropriate form or the amount of drug salt that can be added to the reservoir. It is one objective of this invention to overcome these limitations by providing electrochemically appropriate ions from a source other than, or in addition to, those supplied by the drug salt so as to enhance agent or drug delivery efficiency.
Subsequent to the work of Untereker et al noted above, several patents have disclosed the use of various means to inhibit the flow of ions competitive with the species to be delivered. U.S. Pat. No. 4,722,726 to Sanderson et al discloses an iontophoresis device having an ion mobility inhibiting means (ie, a discrete layer of ion exchange membrane material) disposed between, for example, an electrode/electrolyte solution and a source of the ionic species to be delivered, ie, a drug solution. The ion exchange membranes used by Sanderson et al included the AR103-QZL membrane sold by lonics, Inc. and Raipore 4010 and 4035 membrane sold by RAI Research Corp. A device of the Sanderson et al patent has electrodes which generate hydronium ions and hydroxyl ions during its operation. Thus, the purpose of Sanderson's ion-exchange membrane is to inhibit the passage of ions of similar charge (ie, similar to that of the drug ion) from the electrode/electrolyte solution to the drug solution where they could compete. However, Sanderson et al do not attribute any significance to the selection of the ion exchange medium counter ion. Of particular significance is the fact that the ion exchange membrane disclosed by Sanderson et al is selectively permeable to ions having a charge which is opposite the charge of the drug species to be delivered. To function properly, the ion exchange material must provide a continuous barrier to the passage of ions carrying the same charge as the drug ion.
U.S. Pat. No. 4,731,049 to Parsi discloses an iontophoresis device employing a drug reservoir in which the drug to be delivered is initially bound to an ion exchange medium or an immobilized ligand affinity medium. Ions such as hydrogen (H.sup.+), sodium, potassium, hydroxyl, chloride, and sulfate ions are generated at the electrode or provided by an ion reservoir and are exchanged for the bound drug ions, thereby releasing the drug ions for delivery into the patient's body. Parsi discloses a donor electrode assembly having a hydrophilic polymer-based electrolyte reservoir and drug reservoir layers, a skin-contacting hydrogel layer, and optionally one or more semipermeable membrane layers. The ion exchange media is disclosed to be in the form of beads, powder, packed fibers, woven or knit fibers, microporous or macromolecular resin or liquid resin. Parsi employs electrodes which are electrochemically catalytic, ie, the electrodes are composed of materials (eg, carbon, graphite or metal, such as platinum group metals) which catalyze the electrochemical reaction as described above. Parsi is limited in its application to systems where drug can be bound to an ion exchange resin or medium or an immobilized ligand affinity medium, and for this reason, must possess a charge opposite that of the drug ion. U.S. Pat. No. 4,915,685 to Petelenz et al discloses a system closely related to that disclosed by Parsi.
U.S. Pat. No. 4,927,408 to Haak et al discloses an electrotransport system having a novel donor electrode pad. The pad comprises an agent reservoir, and an electrolyte reservoir separated by a selectively permeable membrane. Microporous polymers, ie, membranes, which are selectively permeable based on the size of the permeating species and ion-exchange membranes which are selectively permeable based on the charge of the permeating species, are disclosed to be useable in the electrode pad of Haak. The charge selective membranes of Haak can be selected to bind, eg, by ion-exchange or chelation, particularly interfering or undesirable species. For example, interfering metals can be removed by this expedient.
Related to the above Haak et al '408 patent is International Application No. WO91/16943 which provides substantial additional detail regarding selectively permeable membranes which are selective for the particular size or molecular weight of the diffusing species.
European Patent Application WO91/15260 (PCT/US91/02030) discloses, in one embodiment, an iontophoretic device having a two layer active electrode element. A single layer active electrode element embodiment also is disclosed. In the embodiments disclosed in the '15260 application, layers of anionic, cationic or amphoteric polymers are used. In a preferred structure, an impermeable layer is interposed between the two layers of the electrode. Enhancement of shelf life is a particular objective of the '15260 application.
U.S. Pat. No. 4,585,652 to Miller et al discloses delivery of bioactive substances using an electrode comprising a polymer which is "charged" or conductive and which can be electrochemically cycled between a charged and a neutral or insulating state. In the charged state, the polymer is located with bioactive counter ions which are delivered when the polymer is cycled to the neutral state. An example of a charged polymer is poly(vinylferrocene). Examples of conductive polymers are poly(pyrroles), substituted poly(thiophenes), and similar poly(heterocyclic) materials.
U.S. Pat. No. 5,057,072 to J. B. Phipps discloses an iontophoresis electrode which uses a current distribution member and a drug reservoir containing an ionic drug. The current distribution member is separated from the drug reservoir by a membrane or a material selective for ions having a charge opposite to the charge of the drug to be delivered. The cation or anion selective layer or coating of material is applied directly to the current distributing member and prevents the migration into the drug reservoir of ions produced during the oxidation or reduction of the current distributing member.
U.S. Pat. No. 5,084,008 to J. B. Phipps discloses an improved iontophoresis electrode having a current distribution member in direct or intimate contact with a salt layer or an ion source layer. In direct or intimate contact with the salt layer or ion source layer is a size selective membrane (ie, a semipermeable membrane) or a material which is charge selective for ions having a charge opposite to the charge of the drug to be delivered. This improved structure of the iontophoresis electrode is preferably employed using a current distributing member which is itself oxidized or reduced during the process of drug delivery.
The above patents which disclose the utilization of charge selective layers or membranes to enhance device efficiency operate on the theory of Donnan exclusion. Donnan exclusion, in the case of a charge selective membrane (eg, an ion-exchange membrane), means that the fixed charge of the membrane reduces the likelihood that ions or molecules having a similar charge from passing through the membrane due to electrostatic repulsion. The type of fixed charge, and the charge density within the ion pathways favor the passage of species having definable characteristics, ie, a charge which is opposite the fixed charge on the membrane. Utilization of the principle of Donnan exclusion, in the context of an electrotransport device having a charge selective membrane, has the drawback of tending to create polarization within the entire device or within a device component. An increase in polarization tends to increase the voltage necessary to deliver agent or ion. A voltage increase within an electrotransport device normally requires an increase in the number of batteries to operate the device and therefore an increase in device size, device complexity, device cost or a combination of these factors.
Size exclusion, in the case of a size selective membrane, means simply that the pore size of the membrane is too small to permit specific molecules or ions to pass. Physical size or molecular weight restriction prevents or hinders the passage of species through the membrane. Utilization of size selective membranes also can create polarization as discussed above if the "excluded" species tend to have the same (+/-) charge.
The present invention overcomes the problems encountered in the prior art and is not suggested or disclosed in the references alone or in combination. Moreover, utilization of the present invention tends to permit smaller, less complex and less expensive electrotransport devices to be built. In addition, the present invention allows utilization of a wider variety of salts and lower drug content than is possible with prior art devices.